SGER: The Initiation of Mammalian Puberty: Transcriptional Regulation by POU-Domain Genes

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There is very little doubt that one of the most meaningful events in the life span of an individual is the acquisition of puberty. Over the years, extensive efforts have been devoted to unravel the neuroendocrine mechanisms underlying this stage of development. Because the neuroendocrine mechanisms involved in the control of puberty are exceedingly complex, progress, to date, has been slow. It is clear, however, that the hypothalamic-pituitary-gonadal axis is the anatomical and functional core of the process. Moreover, puberty does not result from an isolated event, but is rather the consequence of a cascade of interdependent processes initiated very early in development. Within this framework, the initiating events are thought to occur in the brain, where they result in the synchronous activation of neurons that secrete luteinizing hormone-releasing hormone (LHRH). Although the onset and progression of puberty depends upon the increased production and secretion of LHRH, little is known about the molecular and cellular events that activate this event. Dr. Ojeda is one of the few scientists attempting to tackle this intricate and perplexing problem. With this Small Grant for Exploratory Research (SGER), he will define the gene hierarchy controlling within the brain the events underlying the initiation of puberty. Dr. Ojeda will examine whether the POU-domain family of homeobox genes are "upstream" components of the hierarchy of genes controlling neuronal functions relevant to the pubertal activation of the LHRH neuronal network. The genes are likely candidates because they are abundantly expressed in the embryonic hypothalamus, the brain region where LHRH neurons are primarily localized. Moreover, the expression of some of the genes persist in this LHRH region during post-natal development and even in adulthood. Dr. Ojeda will use an experimental model in which hypothalamic lesions are used to accelerate puberty in immature females. The results will not only impact greatly on our understanding of mammalian puberty but would open new avenues for exploring the fundamental role that regulatory genes play in the nervous system.